regulatory rights & legal vehicles in medical...
TRANSCRIPT
Regulatory Rights & Legal Vehicles in
Medical Product Development
From Discovery to Commercialization: Strategizing for Success
FLC 2015 National Meeting, Denver Colorado
Jeremiah J. Kelly, Esq., MPP
Attorney for Medical Product Development &
Regulation
OSJA, USAMRMC
Agenda
• Part I: Understanding the Risks
• Part II: The FDA Regulatory Landscape
• Part III: Comparison of Legal Agreement Vehicles &
Associated Rights
• Part IV: Best Practices
Understanding the Risks
• Product development and Tech Transfer missions require
strategic thinking regarding:
– Proper evaluation of the FDA regulatory landscape (sponsor
responsibilities, unique approval mechanisms, marketing
exclusivity)
– Correct selection of legal instrument (assistance agreement,
contract, CRADA, OTA or a combination)
– Including proper terms/clauses in our legal agreements to
ensure protection of intellectual property (patents, technical
data, etc.) or ability to recover rights licensed
• Failure in any one of these areas creates risk to the product
development effort or the tech transfer mission.
Understanding the Risks
• Ideally, an advanced developer has the “Trifecta”:
– Patent rights
– Technical Data rights
– FDA Sponsorship/Holdership
• We don’t always operate in ideal world:
– We leverage private resources to achieve mission
– Collaborators fail, terminate programs for business reasons,
are acquired/merged, go bankrupt
– Our authorities are cumbersome & not ideally built for the
regulatory environment.
Understanding the Risks
• Goals:
– Maximize the use of existing authorities to secure best
position possible for the investment made
– Take innovative approaches to protect the government’s
interest and achieve the mission.
• Combining legal instruments
• Innovative clauses
• Use current authorities correctly
What are Regulatory Rights?
• General term used to describe the benefits that accrue to
the “Sponsor” or “Holder” of a regulatory application.
• Includes:
– exclusive standing and control before FDA
– special designations or review mechanisms given to the
regulatory application
– marketing exclusivity awarded upon approval
– priority review vouchers that are transferrable upon approval
– ability to supplement applications
Statutory Framework for
FDA Regulated Products
Drugs
• Investigational Use
Application
– IND
• Pre-market Approval
Applications
– §505(b)(1) NDA
– §505(b)(2) NDA
– §505(j) ANDA
Biologics
• Investigational Use
Application
– IND
• Pre-market Approval
Applications
– §351(a) BLA (PHSA)
– §351(k)(2)(A) Biosimilar
– §351(k)(2)(B)
Interchangeable Biosimilar
Statutory Framework for
FDA Regulated Products
Medical Devices
• Investigational Use Application
– IDE (21 CFR 812)
– Abbreviated IDE
– Exempt
• Pre-market Approval
Applications
– §510(k) Pre-marketing Notification
(21 CFR 807(e))
• Some Class I (general), ost Class II
(general & special controls)
• SE, NSE, Revised de novo process
– §515 Pre-market Approval
Application (PMA) (21 CFR
814)
• Class III (special controls
insufficient)
– Exempt
– Humanitarian Device
Exemption
Marketing Exclusivity
• What is it?
– If marketing exclusivity granted, FDA will not
approve certain applications for same drug
product until the expiration of exclusivity period
– Each exclusivity differs in what type of application
it will bar.
– Exclusivity vs. Patent Term
– Goal: balance innovation vs. competition
– Can present unique benefits and challenges to
product developers.
Marketing Exclusivity
• Marketing Exclusivity for Drugs– New Chemical Entity (NCE) – 5 years (21 CFR 314.108)
– New Clinical Information or “Other” – 3 years
– Pediatric (PED) – 6 months’ add-on exclusivity
– Orphan Drug – 7 years (21 CFR 316.31)
– Qualified Infectious Disease Product (QIDP) – 5 years add-on
exclusivity (*NEW*)
– Generic Drug Exclusivity (available for 505(j) applicant only) – 6
months
• Marketing Exclusivity for Biologics– New Biologic – 12 years
– Interchangeable Biosimilar – 1 year
Marketing Exclusivity
• Marketing Exclusivity for Drugs– New Chemical Entity (NCE) – 5 years (21 CFR 314.108)
• BAR: 505(b)(2) or 505(j) applicant; not full 505(b)(1) NDA (see
§505(c)(3)(E)(ii); §21 CFR 314.108(b)(2))
• Request in NDA
– New Clinical Information or “Other” – 3 years
• Available to 505(b)(2) [21 CFR 314.108(b)(4)] Applicant or as
Supplement [21 CFR 314.108(b)(5)]
• BAR: 505(b)(2) or 505(j) applicant; not full 505(b)(1) NDA
– Pediatric (PED) – 6 months add-on exclusivity
• Awarded for conduct of pediatric clinical studies in response to
written request
• Only extends; does not create additional bars
Marketing Exclusivity
• Marketing Exclusivity for Drugs– Orphan Drug – 7 years (21 CFR 316.31)
• First approval of drug or biologic approved
• BARS: any application [included full-scale NDA or BLA] that includes
the active ingredient for that indication
• Request before filing of NDA/BLA, as early as possible.
– Generic Drug Exclusivity – 6 months
• BARS: subsequent 505(j) ANDA for 180 days/6 months.
Marketing Exclusivity
• Marketing Exclusivity for Drugs• Qualified Infectious Disease Product (QIDP) – 5 years add-on
exclusivity
• Title VIII of FDASIA entitled “Generating Antibiotic Incentives Now
(GAIN)”
• QIDP = "an antibacterial or antifungal drug (*) for human use
intended to treat serious or life-threatening infections, including
those caused by: (1) an antibacterial or antifungal resistant
pathogen, including novel or emerging infectious pathogens; or (2)
qualifying pathogens."
• BARS: same as underlying exclusivity period; BUT applicable to
drugs only (potentially even in instance where it’s a biologic
obtaining orphan status); not applicable to 3-year New Clinical
Information exclusivity; issue w/ interpreting re: supplements where
original NDA was eligible, but came before GAIN.
• Rulemaking due July 2014
Marketing Exclusivity
• Marketing Exclusivity for Biologics– New Biologic – 12 years
• Biologics Price Competition and Innovation Act of 2009 (BPCI),
Public Law 111-148, enacted as part of the Affordable Care Act
on March 23, 2010, amended §351 of the Public Health Service
Act (PHSA)
• BAR: licensure of biosimilar or interchangeable version of a
reference product. 42 USC §262(k)(7)(A); bars any abbreviated
application for 4 years; does not bar submission of full-scale BLA
– Interchangeable with Reference Biologic – 1 year
• BAR: subsequent interchangeable product for that reference
product (42 USC §262(k)(6)
• Decouples from patent litigation, unlike Hatch-Waxman
• Duration may extended up to 3.5 years if patent litigation is
ongoing
Special Review Designations
& Approval Pathways • Special Designations
– Fast Track
– Breakthrough Therapy
– Priority Review (including voucher programs)
– Orphan Drug
• Special Approval Pathways
– Accelerated Approval
– Animal Rule
Guidance for Industry: Expedited Programs for Serious
Conditions – Drugs and Biologics (Draft), U.S. Food and Drug
Administration, June 2013
Special Review Designations
• Fast Track Designation
– Where: §506(b) of the FD&C Act, part of FDAMA in 1997,
amended by Section 901 of the Food and Drug Safety and
Implementation Act (FDASIA)
– Qualifying Criteria:
• Drug intended to treat a serious condition AND non-clinical or
clinical data demonstrate the potential to address an unmet
medical need or a drug has been designated as a qualifying
infectious disease product (QIDP).
– Request w/IND, no later than pre-NDA/BLA meeting, FDA
response w/in 60 days
– Features: expedited development and review through rolling
review process.
Special Review Designations
• Breakthrough Therapy Designation
– Where: §506 (a) of the FD&C Act, added by §902 of FDASIA
– Qualifying Criteria:
• Drug intended to treat a serious condition AND preliminary
clinical evidence indicates that the drug may demonstrate
substantial improvement on a clinically significant endpoint(s)
over available therapies.
– Request: w/IND, no later than End of Phase 2 Mtg., FDA
response w/in 60 days
– Features: all fast-track features, intensive guidance on
efficient drug development during IND, as early as Phase 1,
organizational commitment w/ senior leadership (“all hands
on deck approach”)
Special Review Designations
• Priority Review
– Where: Prescription Drug User Fee Act (PDUFA) of 1992
– Qualifying Criteria:
• Application (original or efficacy supplement) for drug that treats a
serious condition AND if approved would provide a significant
improvement in safety or effectiveness OR
• Supplement for labeling change pursuant to a report on a
pediatric study under Pediatric Research Equity Act OR QIDP
OR any application or supplement submitted with a Priority
Review Voucher
– Request with BLA, NDA or efficacy supplement, FDA
response in 60 days
– Features: 6 month review clock vs. normal 10 month
Special Review Designations
• Orphan Drug Designation
– Where: §526 of the FD&C Act, added by Orphan Drug Act, 21
CFR 316.20(b)(8) – 21 CFR 316.21.
– Qualifying criteria:
• Sponsor must submit documentation demonstrating that “the
disease or condition for which the drug is intended affects fewer
than 200,000 people in the United States or, if the drug is a
vaccine, diagnostic drug, or preventative drug, the persons to
whom the drug will be administered in the United States are
fewer than 200,000.”
– Features: no PDUFA fee, 7 years of marketing exclusivity
(active ingredient + indication), will typically receive fast track
and/or priority review, but this is not automatic.
Incentives
• Priority Review Vouchers
– Applications for drugs for the treatment or prevention of certain
tropical diseases under §524(a)(3) and (4) of the FD&C Act
• Applicable to both 505(b)(1) NDAs or 351 BLAs
• Enumerated “tropical disease” includes malaria, cholera, dengue,
leishmaniasis, and “any other infectious disease for which there is
no significant market in developed nations and that
disproportionately affects poor and marginalized populations”
• Not applicable to any active ingredient approved under 505(b)(1)
NDA or 351 (BLA).
• Transferable by contract; 1 year notice before use
– Applications for drugs to treat of rare pediatric diseases as
defined under 529(a)(3) of the FD&C Act
Special Approval Pathways
• Accelerated Approval
– Where: 21 CFR 314, Subpart H (for drugs); 21 CFR 601,
Subpart E (for biologics); §506(c) of the FD&C Act as amended
by §901 of FDASIA.
– Qualifying Criteria:
A drug that treats a serious condition AND provides meaningful
advantage over available therapies AND demonstrates an effect on
a surrogate endpoint that is reasonably likely to predict clinical
benefit OR on a clinical endpoint that can be measured earlier than
an effect on irreversible morbidity or mortality (IMM) that is
reasonably likely to predict an effect on IMM or other clinical benefit
(i.e., intermediate clinical endpoint).
– Discuss w/review division as early as possible
– Features: based on surrogate; post-marketing study
commitments to verify (Phase IV)
Special Approval Pathways
• Animal Rule
– Where: 21 CFR §314.600 (Subpart I)
– Qualifying Criteria:
• new drug or biologic that intended to “treat or prevent serious or life
threatening conditions caused by exposure to lethal or permanently
disabling toxic biological, chemical, radiological, or nuclear
substances” and where “human efficacy studies cannot be
conducted because it would be unethical….and field trials…have not
been feasible.” 21 CFR 314.600
– Discuss w/review division as early as possible
– Features:
• FDA will rely on animal studies to show efficacy when, inter-alia,
effect is demonstrated in more than 1 animal species predictive of
the response in humans; Animal study endpoint is related to the
desired endpoint in humans ,
• Post-market studies when exigency emerges. See 21 CFR
314.610.(b)(1)
Regulatory Considerations
• Know the full value of your regulatory position (likely designation,
exclusivity) before conceding Sponsorship to a development
partner
• Avoid conceding regulatory sponsorship too early; best to retain
control of the development effort until partner’s effort is mature
enough to engender confidence
• Be clear about who is the Sponsor
• If Sponsorship is conceded, leverage contributions to effort to
ensure ability to (i) remain actively involved in FDA meetings and
communications; (ii) assume Sponsorship/Holdership if there are
product development failures; and (iii) obtain necessary licenses
to IP and technical data for commercial development.
• Align plan with mission (advanced development or both)
Choosing the Correct Legal Vehicle
• USAMRMC utilizes five (5) types of legal instruments to
accomplish its product development mission:
– Assistance Agreements (grants and cooperative agreements)
– Contracts
– Cooperative Research and Development Agreements
(CRADAs)
– Other Transaction Authority (OTAs)
– License of Federal Technology (covered by other presentations)
– Agreements Differ on:
• Purpose and use of funds
• Allocation of Technical Data Rights
– Restricted
– Federal or Government Purpose
– Unlimited
Assistance Agreements
• Purpose:
– Includes grants and cooperative agreements. Cooperative
agreements require “substantial involvement” by the awarding
agency; grants do not.
– A mechanism to provide government funding to a project, the
completion of which is in the public interest.
– inappropriate for the acquisition of a good or service.
• Where: 10 USC §2358(b)(1), 15 USC §3701, DoDGARS, 32
CFR §32.36 (nonprofit); 32 CFR §34.25 (for profit)
• Process: Funding Opportunity Announcement (PA or BAA);
merit-based/competitive
– “Best efforts” if awarded in a research area
Assistance Agreements
• Features & Limitations:
– Money out
– Federal Purpose Rights (FPR) in technical data
• “(1) obtain, reproduce, publish or otherwise use the data
directly produced under an award; and (2) [a]uthorize others
to receive, reproduce, publish, or otherwise use such data for
Federal purposes.” 32 CFR 32.36(c)
• “Federal purposes” ill-defined
– Ability to require delivery of data is limited
– “Best efforts” if awarded in a research area
Contracts
• Purpose:
• A contract is a legal instrument used for the acquisition of
goods or services.
• Where: 10 USC §2358(b)(1)
• Process: Full and open competition with exceptions for
Broad Agency Announcement (BAA) and Sole/Limited
Source Justification
• Features & Limitations:
– Money out
– Unlimited Rights in Technical Data
– Cumbersome and Lengthy Process
– Must be utilized correctly to obtain full benefit of vehicle
Contracts
• Utilize the Correct Clauses
– For patents, use FAR 52.227-11 (FAR 52.227-13 is never
used; exceptional circumstances)
– DoD does not use FAR 27.4 for technical data, but rather the
guidance at DFAR 227.71 and 227.72 (48 CFR §227.400)
• DFAR Non-commercial Technical Data Rights Clause 252.227-
7013/7014
• SBIR Technical Data Rights Clause 252.227-7018
• DFAR Commercial Technical Data Rights Clause 252.227-7015
– Government receives 1 of 3 licenses (but may negotiate
license as part of the contract, see DFAR 227.7102-2(b));
license generally determined by the source of funds used.
• Unlimited (developed exclusively at government expense)
• Government Purpose/Use (mixed funding)
• Limited/Restricted (developed exclusively at private expense)
Contracts
• Ensure Data Order & Delivery
– Order and delivery accomplished by Contract Data
Requirements List (CDRL), DD Form 1423, combined with
the appropriate Data Item Description (DID), DD Form 1664
– CDRL = data order form
– DID = describe data format and content requirements
• Getting it Right From RFP Forward:
– Include Section C, Statement of Work
– Include in Section F (Deliveries or Performance, CLINs)
– Include Section L (Instructions, Conditions and Notices to
Offerors)
– Include Section M (Evaluation Factors for Award)
– Cite CDRL in Section J (List of Attachments)
– Prepare to Review Markings: Nonconforming, Unjustified
Contracts: DFAR 252.227-7013
• Technical Data (48 CFR 252.227-7013(a)(15))
– “recorded information, regardless of the form or method of the recording
of a scientific or technical nature (including computer software
information). The term does not include computer software or data
incidental to contract administration, such as financial or management
information.”
• Detailed Manufacturing or Process Data (48 CFR 252.227-7013(a)(6))
– “technical data that describe the steps, sequences and conditions of
manufacturing, processing or assembly used by the manufacturer to
produce an end item or component or to perform a process.”
• Form, Fit and Function Data (48 CFR 252.227-7013(a)(11))
– “technical data that describes the required overall physical, functional,
and performance characteristics (along with the qualification
requirements, if applicable) of an item, component, or process to the
extent necessary to permit identification of physically and functionally
interchangeable items.”
Contracts
• What technical data do I need to consider:
– Manufacturing Data
• GMP or QSR certificate of compliance
• Batch/production records
• Tech transfer report for process development, validation reports
• All testing reports, certificates of analysis
• Stability reports
• Cold chain documents
• Equipment identification
• Cross reference to Drug Master Files (DMFs)– The types of DMFs are:
» Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)
» Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or
Drug Product
» Type III Packaging Material
» Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
» Type V FDA Accepted Reference Information
Contracts
• What technical data do I need to consider:
– Non-clinical Data
• GLP certificate of compliance
• Study report
• Site/staff qualification
Contracts
• What technical data do I need to consider:
– Clinical Data (typically in Clinical Trial Agreement)
• GCP certificate of compliance
• IRB approval
• Monitoring reports
• Protocol & amendments
• Regulatory filings, correspondence
• Site/staff qualification
• Clinical database, data sets
• Statistical Analysis Plan & Data Management Plan
– Objectives, endpoints, sample size, tables-listings and figures
(TLF)
– Case Report Forms
– Final Clinical Study Reports
Contracts: DFAR 252.227-7013
• Best Practices
– Have contactor assert rights in technical data prior to award in
an assertion list (DFAR 252.226-7013(e))
– Explore specifically negotiated rights (DFAR 252.226-7013(b)(4))
– Ensure unlimited rights coverage (DFAR 252.226-7013(b))
• (i) “data related to item, component or process developed exclusively at government
expense”
• (ii) “studies, analysis, test data or similar data produced for this contract when the
[…data or similar work] was specified as an element of performance”
• (iii) “created exclusively with government funds in performance of a contract that does
not require development, manufacture, construction or production of items, components,
or process.”
• (iv) Form, fit and function data
• (v) operation, maintenance, installation or training data (other than detailed
manufacturing or process data)
• (vi) Corrected or changed data from the government
Contracts: DFAR 252.227-7013
• Best Practices
– Ensure unlimited rights coverage
• Note potential conflict between subsection (ii) and (iii)/(v); there
seems to be greater protection for “detailed manufacturing or
process data”
– Proper Markings & Legends
• Must conspicuously and legibly mark GPR, Limited or Special on
each page
• Unjustified vs. Non-Conforming
• Validation of Restrictive Marking clause (DFAR 252.227-7037)
– Deferred Delivery & Order
• DFAR 252.227-7026
• Expensive
CRADA• Purpose:
• A Cooperative Research and Development Agreement (CRADA) is a
unique legal mechanism for the government to partner with any
outside entity for a stated research collaboration.
• Where: 15 USC §3710a, AR 70-57 (T2), DODI 5535.8
• Process: Discretionary and flexible, no competition, ORTA
• Features & Limitations:
– No money out (but goods and services out); money and
nearly everything else in
– Regulatory rights and Technical Data rights subject to
negotiation
– Must be a defined research collaboration
– Limited to designated federal laboratories w/CRADA authority
OTA• Purpose:
• Transactions where assistances agreements and contracts are not
suitable (these are no procurement contracts)
• Where: 10 USC §2371 (see also §845 of the NDAA of 1994
and subsequent NDAAs)
• Process: flexible, competition to the maximum extent
practicable
• Features & Limitations:
– money out
– Prototype projects, but recently opened to larger application
– No FAR-based cost-accounting standards
– No FAR-based restrictions on Bayh-Dole and Technical Data Rights
subject; generally, subject to negotiation
– Nontraditional defense contractors
– Novel, untested
Best Practices to Mitigate Risk
• Remember to:
– Know the regulatory landscape, properly value the potential
– Know your IP, Technical Data Needs
– Know the agreements you need and how to use them to their
maximum utility
• Innovate within legal boundaries:
– Combining legal instruments for “seamless approach”
– Innovative clauses (get deviations where needed)
– Use current authorities correctly
Best Practices to Mitigate Risk
• Aggressive Evaluation Sub-Factors for Open Data Rights
– Higher Rating for Open Data Rights Proposals (DFARS
227.7103-10(a)(5))
– Separate Costing/Proposals
• Increased and Efficient Use of Contract Vehicle over
Assistance Agreement
– Use the contract vehicle to its maximum utility
• Cost-sharing Approach
• Transition Cooperative Agreements to Sole/Limited Source
Contracts
Contact Information
• Jeremiah J. Kelly, Esq., MPP
Attorney for Medical Product Development & Regulation,
Office of the Staff Judge Advocate,
U.S. Army Medical Research and Materiel Command
Building 521, Room 13A, Fraim Street, Ft. Detrick, MD
e-mail: [email protected]
phone: (301) 619-6554